ABSTRACT

IMPORTANCE Hormonal contraceptives are widely used but how breast cancer risk differs
by hormonal content remains unclear.

OBJECTIVE To estimate the difference in breast cancer risk associated with different hormonal
contraceptive formulations.

DESIGN, SETTING, AND PARTICIPANTS This Swedish nationwide, population-based cohort
study was conducted using linked national registers. All adolescent girls and women aged 13
to 49 years residing in Sweden as of January 1, 2006, with no history of breast cancer,
ovarian cancer, cervical cancer, uterine cancer, bilateral oophorectomy, or infertility treatment
were included and followed up from 2006 to 2019. Individuals were censored on meeting an
exclusion criterion, reaching age 50 years, or study end, whichever occurred first. Data were
analyzed from November 2023 to August 2025.

EXPOSURE Ever use and duration of use of hormonal contraceptives, categorized by hormone
formulations and route of administration.

MAIN OUTCOMES AND MEASURES Time-dependent Cox regressionwas used to estimate
hazard ratios (HRs) with 95%CIs for incident cases of in situ and invasive breast cancer.

RESULTS Among 2095 130 adolescent girls andwomen (median [IQR] age at diagnosis,
45 [41-48] years) whowere followed up for 21020846 person-years, 16 385 breast cancer
cases occurred. Ever use of any hormonal contraceptivewas associated with increased
breast cancer risk (HR, 1.24; 95%CI, 1.20-1.28), corresponding to 1 additional case
per 7752 (95%CI, 5350-14070) users, with both combined (HR, 1.12; 95%CI, 1.07-1.17)
and progestin-only formulations (HR, 1.21; 95%CI, 1.17-1.25) being associated. Higher risk
was associated with oral desogestrel-only formulations (HR, 1.18; 95%CI, 1.13-1.23) and oral
desogestrel-combined formulations (HR, 1.19; 95%CI, 1.08-1.31), aswell as implants
containing etonogestrel, desogestrel’s activemetabolite (HR, 1.22; 95%CI, 1.11-1.35),
compared to levonorgestrel-containing combined pills (HR, 1.09; 95%CI, 1.03-1.15) and
levonorgestrel, 52mg, intrauterine system (HR, 1.13; 95%CI, 1.09-1.18). No statistically
significant increased riskwas observed for medroxyprogesterone acetate injection,
etonogestrel vaginal ring, or combined oral drospirenone, despite having many users.

CONCLUSIONS AND RELEVANCE Findings of this cohort study highlight that breast cancer risk
varies substantially by progestin content in hormonal contraceptives, providing valuable
insights to support more informed contraceptive prescription.